Vaccines based on the production of neutralizing antibodies are among the most successful and cost effective public health interventions ever devised, and they have clearly been demonstrated to have worldwide applicability. This project seeks to use a vaccine induced antibody-based approach to develop entry-inhibitors targeting an HIV-1 coreceptor, CCR5, which plays a critical role in viral replication and pathogenesis. We have previously demonstrated that virus-like particle (VLP) based immunogens can abrogate the normal mechanisms of B cell tolerance and efficiently induce strong humoral immune responses against target self-antigens, including CCR5. In preliminary studies, pig-tailed macaques immunized with CCR5 conjugated VLPs made anti-CCR5 IgG which could block viral replication in vitro. Upon challenge with a CCR5-tropic SHIV virus, vaccinated macaques exhibited reduced viral loads and time to control of viremia relative to control macaques. We now propose to more fully evaluate the correlates and effects of autoantibody induction by CCRS-conjugatedVLPs using a murine model. In specific aim 1, we will test the compatibility of different adjuvants and immunization regimens and the role of T help in the induction of high titer systemic and mucosal anti-CCR5 antibody responses in mice. In specific aim 2, we will assess the effects of these antibodies on chemokine function using in vitro assays and in vivo model systems. In specific aim 3, we will develop vaccines targeting multiple domains of primate CCR5 and examine the ability of these antigens to induce anti-CCR5 antibodies that inhibit the replication of diverse SIV and HIV isolates. These studies seek to more fully characterize both the potential and the risks of this novel immunization strategy, which is based on the induction of antibody responses against CCR5, a self-antigen. The ultimate goal of these studies is to add a vaccine-based approach to the arsenal of HIV anti-virals.